Inclusion of epitopes that expand high avidity CD4+ T cells transforms sub-protective vaccines to efficacious immunogens against virulent Francisella tularensis

摘要

T cells are the immunological cornerstone in host defense against infections by intracellular bacterial pathogens, such as virulent Francisella tularensis (Ftt). The general paucity of novel vaccines for Ftt over the past 60 years can, in part, be attributed to the poor understanding of immune parameters required to survive infection. Thus, we developed a strategy utilizing classical immunological tools to elucidate requirements for effective adaptive immune responses directed against Ftt. Following generation of various Francisella strains expressing well-characterized lymphocytic choriomeningitis virus (LCMV) epitopes, we found that survival correlated with persistence of antigen-specific CD4⁺ T cells. Function of these cells was confirmed in their ability to more effectively control Ftt replication in vitro. The importance of understanding the antigen-specific response was underscored by our observation that inclusion of an epitope which elicits high avidity CD4⁺ T cells converted a poorly protective vaccine to one that engenders 100% protection. Together, these data suggest that improved efficacy of current tularemia vaccine platforms will require targeting appropriate antigen-specific CD4⁺ T cell responses and that elucidation of Francisella epitopes that elicit high avidity CD4⁺ T cell responses, specifically in humans, will be required for successful vaccine development.